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Review
, 23 (1), 99-139

Reduced Vancomycin Susceptibility in Staphylococcus Aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

Affiliations
Review

Reduced Vancomycin Susceptibility in Staphylococcus Aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

Benjamin P Howden et al. Clin Microbiol Rev.

Abstract

The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) over the past decade has provided a challenge to diagnostic microbiologists to detect these strains, clinicians treating patients with infections due to these strains, and researchers attempting to understand the resistance mechanisms. Recent data show that these strains have been detected globally and in many cases are associated with glycopeptide treatment failure; however, more rigorous clinical studies are required to clearly define the contribution of hVISA to glycopeptide treatment outcomes. It is now becoming clear that sequential point mutations in key global regulatory genes contribute to the hVISA and VISA phenotypes, which are associated predominately with cell wall thickening and restricted vancomycin access to its site of activity in the division septum; however, the phenotypic features of these strains can vary because the mutations leading to resistance can vary. Interestingly, changes in the staphylococcal surface and expression of agr are likely to impact host-pathogen interactions in hVISA and VISA infections. Given the subtleties of vancomycin susceptibility testing against S. aureus, it is imperative that diagnostic laboratories use well-standardized methods and have a framework for detecting reduced vancomycin susceptibility in S. aureus.

Figures

FIG. 1.
FIG. 1.
Overview of some general cell wall characteristics of VSSA and VISA strains showing the key regulatory elements linked to intermediate-level vancomycin resistance, as uncovered by comparative genomics and genetic studies. (A) VSSA strain in the absence of vancomycin showing a normal peptidoglycan (PG) layer, with the production of protein A and normal capsular polysaccharide expression. Also shown is the division septum, where cell wall growth occurs. The lipid II-linked PG precursors assemble at the division septa, and the dipeptide moiety of lipid II is the lethal target of vancomycin. (B) VISA strain with mutations in either the graRS, vraSR, or walKR operon (or all) that might lead to their respective regulons remaining in an activated “locked-on” or otherwise modified state. The consequence of this modification includes cell wall thickening, decreased autolysis, reduced protein A production, increased capsule expression, increased d-alanylation of teichoic acids, and reduced agr activity.
FIG. 2.
FIG. 2.
Model depicting the site of vancomycin activity in the division septum and the changes associated with the VISA phenotype. The path of vancomycin to its lethal target (lipid II) should be through the division septum. In vancomycin-intermediate cells (Vanr), the rate of diffusion of vancomycin molecules to the septal tip is decreased, lowering the effective concentration of antibiotic that reaches the lipid-linked peptidoglycan precursor (lipid II) at the site of cell wall synthesis, per unit time, and therefore tilting the balance in favor of continued cell wall synthesis. This model implies that vancomycin efficiency varies during the cell cycle, as the path from the outside of the cell to the lethal targets is shorter when the septum starts to be formed and longer when septum synthesis approaches completion. (Adapted from reference with permission.)
FIG. 3.
FIG. 3.
Example of population analysis profile curves for vancomycin-susceptible and heterogeneous vancomycin-intermediate S. aureus strains. The in vivo evolution of the resistant phenotype is depicted with a shift in the PAP curve to the right, with SmaI-digested pulsed-field gel electrophoresis patterns being identical for paired isolates from the same patient. (Adapted from reference .)
FIG. 4.
FIG. 4.
Correlation between vancomycin Etest MIC and heteroresistance (defined by macromethod Etest) for MRSA blood culture isolates collected between 1996 and 2006. The shaded area represents the percentage of isolates that are hVISA isolates at a given MIC and demonstrates that strains with an Etest MIC as low as 1.5 μg per ml also demonstrated heteroresistance. (Adapted from reference with permission.)
FIG. 5.
FIG. 5.
Example of the cell wall and capsule changes that occur in hVISA and VISA strains in paired isolates from patients with persistent infections. The top panel demonstrates significant cell wall thickening in VISA strains compared to VSSA strains, while the bottom panel demonstrates significant increases in the expression of capsule by using an anticapsule type 8 immunoblot and serial dilutions of crude capsule extracts from paired VSSA and VISA strains. (Adapted from references and , the latter of which was published under an open-access license agreement.)
FIG. 6.
FIG. 6.
Microarray transcriptional heat map analysis of cell wall stimulon activation of hVISA/VISA (defined by population analysis and vancomycin broth MIC) relative to parental VSSA. Five isolate pairs are included (P1 to P5). For each pair, the hVISA/VISA and VSSA strains were isolated from the same patient. The fold ratio of gene transcription for hVISA/VISA compared to VSSA was calculated from pooled microarray data using The Institute for Genomic Research S. aureus arrays. Divergent transcriptional patterns were observed for the five pairs and demonstrate that for some hVISA/VISA strains, the cell wall stimulon is activated compared to parental VSSA strains, while in others, it is not activated compared to parental strains. HP, hypothetical protein. (Adapted from reference , which was published under an open-access license agreement.)
FIG. 7.
FIG. 7.
Examples of changes in colony morphology that can occur with hVISA and VISA strains. (A) Mixed-colony morphologies from a pure culture of S. aureus from a bile specimen demonstrate remarkable heterogeneity in colony size and hemolytic activity. The small colonies were VISA, while the larger colonies were VSSA. (Reprinted from reference with permission.) (B) Mixed-colony pigmentation in a pure culture of S. aureus, where the yellow colonies were VISA and the gray colonies were VSSA. The different morphologies were identical by pulsed-field gel electrophoresis. (C and D) Subtle changes in colony morphology that occur in VISA strains compared to parental VSSA strains. JKD6009 (C) is a VSSA strain, and JKD6008 (D) is a VISA strain isolated from the same patient after failed vancomycin therapy. The pulsed-field gel electrophoresis patterns were also identical for JKD6008 and JKD6009.
FIG. 8.
FIG. 8.
Examples of Etest methodology used to detect hVISA. (A) Etest GRD result for Mu50 after 48 h of incubation. (B and C) Macromethod (2 McFarland standard) Etest result for Mu50 against vancomycin (VA) and teicoplanin (TP) after 48 h of incubation. Note the microcolonies that are best detected using magnification and are important for interpreting the test result.
FIG. 9.
FIG. 9.
Flow diagram describing the possible approaches to the investigation and management of patients with serious MRSA infections being treated with vancomycin.

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